In 1946, the Institute for the Study of Analgesic and Sedative Drugs awarded a grant to the Laboratory of Industrial Hygiene at New York City's Department of Health to study problems associated with analgesic (pain-relieving) medications. Axelrod and his mentor, Bernard Brodie, were charged with finding out why consumers who used non-aspirin analgesics, such as Bromo Seltzer, were developing an illness known as methemoglobinemia, a non-lethal blood condition. Brodie and Axelrod demonstrated that acetanilide, the main ingredient of these products, was the problem. They suggested that manufacturers replace it with acetaminophen, an analgesic now better known under its brand name, Tylenol. "[It] was my first taste of real research, and I loved it," Axelrod later wrote of his first article, "The Fate of Acetanilide in Man," which was published in the Journal of Pharmacology and Experimental Therapeutics in 1948.
Brodie and Axelrod continued to collaborate on a number of projects related to the metabolism of analgesic drugs including phenacetin, antipyrine, aminopyrine, and dicoumerol. Axelrod noted that dicoumerol appeared in the blood plasma of test subjects in various concentrations, which suggested to him that there were individual and, thus, genetic differences in how people and animals metabolize drugs. This recognition of metabolic difference was a key moment of understanding in Axelrod's early career.
In 1949, Axelrod moved to the National Heart Institute at the National Institutes of Health and continued his research, directing experiments on the effects of ascorbic acid (Vitamin C) on drug metabolism. After working with analgesics, Axelrod became increasingly interested in the "sympathomimetic amines," a phrase coined in 1910 by the British pharmacologists George Barger and Henry Hallett Dale. This group of drugs, which include caffeine, amphetamine, mescaline, and ephedrine, mimics the chemical behavior of hormones in the nervous system, including epinephrine, norepinephrine, dopamine, and serotonin.
From January 1950 through March 1951, Axelrod studied the effects of caffeine on behavior and developed new methods for measuring caffeine metabolism in the blood. Viewers can read, in the Documents section, his experiments with popular coffee brands taken from Axelrod's extensive collection of original laboratory notebooks. Beginning in 1951, Axelrod conducted research on codeine, ephedrine, methamphetamine, and morphine. In 1953 and 1954, he published comparative studies of the metabolism and disposition of these drugs.
Axelrod was also among the first U.S. scientists to conduct scientific experiments on the metabolism of lysergic acid diethylamide-25 (known colloquially as LSD), which he studied in-depth from September 1954 through March 1958. LSD, a hallucinogenic drug, sparked both scientific and legal controversy after its synthesis had garnered significant media attention. Despite the drug's notoriety, Axelrod's research on LSD in the 1950s did not turn him into a figure in the emerging counterculture of the 1960s. He was not, for example, associated with scientists like Timothy Leary, the psychologist who was fired from Harvard University after he promoted LSD use through his famous phrase "tune in, turn on, drop out."